ABSTRACT/PROJECT SUMMARY This proposal systematically characterizes brain efficiency and recruitment in virologically suppressed persons living with HIV (PLWH) and demographically similar HIV uninfected (HIV-) controls. This proposal collects advanced functional neuroimaging that provide critical information about cerebral blood flow (CBF) and brain connectivity (functional connectivity strength; FCS); quantitative measures of immune dysfunction in the blood and cerebrospinal fluid (CSF) (immune activation and immune exhaustion); and neuropsychological performance testing. This overall goal of this proposal is to delineate the interplay between dysfunction in frontal networks and recruitment of compensatory networks that underlie the neuropsychiatric symptoms seen in PLWH. This proposal investigates fundamental questions through two aims. Aim 1 determines the neuroimaging signatures of brain efficiency and recruitment in virologically suppressed PLWH. We hypothesize that PLWH will have increased recruitment of compensatory networks to offset reduced engagement in frontal networks. Among PLWH, we hypothesize that worse neuropsychological performance will be associated with reduced brain efficiency, despite recruitment of compensatory networks . We hypothesize that the presence of immune dysfunction (immune activation and exhaustion) among PLWH will be associated with reduced brain efficiency despite recruitment of compensatory networks. Aim 2 determines the effects of brain efficiency and recruitment on aging in virologically suppressed PLWH. We hypothesize that younger PLWH (< 50 years old) will have a profile of brain efficiency and recruitment that is similar to older HIV- individuals (> 50 years old). Compared to younger PLWH (< 50 years old) older PLWH (? 50 years old) will have reduced brain efficiency despite recruitment of compensatory networks. We hypothesize that this relationship may be mediated by immune dysfunction. Results of this study will provide powerful insight into the pathophysiology of disease and will reveal arenas for future possible interventions in PLWH who have impaired neuropsychological performance.